Plasma membrane calcium pumps are Ca2+—Mg2+-ATPases that use the energy of hydrolysis of ATP to expel cellular Ca2+. Plasma membrane (PM) Ca2+ pumps are present in all mammalian cells. However, either PM Ca2+ pumps or Na+/Ca2+ exchanger (8,9,17) may remove Ca2+ from the cell after activation or during homeostasis, and the precise role of PM Ca2+ pumps remains to be determined. There are no extracellular PM Ca2+ pump inhibitors available to resolve this issue. In contrast, the Na+ pump inhibitors ouabain and digoxin have been pivotal in our understanding of how this pump affects cell function (7, 12). The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) inhibitor thapsigargin, which can diffuse into the cell to act, has also proved very useful in elucidating the role of the SERCA pump (15). PM Ca2+ pumps are encoded by four plasma membrane Ca2+-ATPase (PMCA) genes, and their transcripts can be alternatively spliced (2, 4, 10, 14). The isoform. PMCAlb is most widely expressed. The PM Ca2+ pump protein models show ten transmembrane and five extracellular domains (4). Except for the first putative extracellular domain, their sequences are conserved in different isoforms. All the known functions of the pump are assigned to the cytosolic domains, although mutagenesis of key residues in the PM Ca2+ pump protein shows that transmembrane domains are involved in its activity (5). X-ray diffraction studies of the sarcoplasmic reticulum Ca2+ pump also support a role for transmembrane domains in the pump activity (16). In contrast, it is unknown whether extracellular domains in the PM Ca2+ pump play any role in its function.
There is a need in the art to provide inhibitors of the plasma membrane Ca2+ pump.